5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1 H)-one and processes for their preparation

ABSTRACT

Provided herein are 5-fluoro-4-imino-3-(alkyl/substituted alkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and processes for their preparation which may include the use of an alkali carbonate and an alkylating agent

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 14/584,347, filedDec. 29, 2014, which claims the benefit of U.S. Provisional PatentApplication Ser. Nos. 61/922,582 and 61/922,572, each filed Dec. 31,2013, the disclosures of each are expressly incorporated by referenceherein.

FIELD

Provided herein are 5-fluoro-4-imino-3-(alkyl/substitutedalkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and processes fortheir preparation.

BACKGROUND AND SUMMARY

U.S. patent application Ser. No. 13/090,616, U.S. Pub. No. 2011/0263627,describes inter alia certainN3-substituted-N1-sulfonyl-5-fluoropyrimidinone compounds and their useas fungicides. The disclosure of the application is expresslyincorporated by reference herein. This patent application describesvarious routes to generateN3-substituted-N1-sulfonyl-5-fluoropyrimidinone compounds. It may beadvantageous to provide more direct and efficient methods for thepreparation, isolation, and purification ofN3-substituted-N1-sulfonyl-5-fluoropyrimidinone fungicides and relatedcompounds, e.g., by the use of reagents and/or chemical intermediatesand isolation and purification techniques which provide improved timeand cost efficiency.

Provided herein are 5-fluoro-4-imino-3-(alkyl/substitutedalkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one and processes fortheir preparation. In one embodiment, provided herein is a process forthe preparation of compounds of Formula III:

wherein R₁ is selected from:

and R₂ is selected from:

which comprises contacting compounds of Formula II (shown below) with abase, such as an alkali carbonate, e.g., sodium-, potassium-, cesium-,and lithium carbonate (Na₂CO₃, K₂CO₃, Cs₂CO₃, and Li₂CO₃, respectively)or an alkali alkoxide, for example, potassium tert-butoxide (KO^(t)Bu)and an alkylating agent, such as an alkyl halide of Formula R₂—X,wherein R₂ is as previously defined and X is a halogen, e.g., iodine,bromine, and chlorine, in a polar solvent, such as N,N-dimethylformamide(DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA),N-methylpyrrolidone (NMP), acetonitrile (CH₃CN), and the like, atconcentrations from about 0.1 molar (M) to about 3 M. In someembodiments, a molar ratio of compounds of Formula II to the base isfrom about 3:1 to about 1:1 and a molar ratio of compounds of Formula IIto alkylating agent is from about 1:1 to about 3:1. In otherembodiments, molar ratios of compounds of Formula II to the base andcompounds of Formula II to the alkylating agent of about 2:1 and 1:3,respectively, are used. In some embodiments, the reactions are conductedat temperatures between −78° C. and 90° C., and in other embodiments,the reactions are conducted between 22° C. and 60° C.

It will be understood by those skilled in the an that manipulation ofthe reaction parameters described above may result in the formation ofproduct mixtures comprised of compounds of Formulas II, III, and IV, asshown in Scheme 1, wherein the ratios of compounds of Formulas II, III,and IV formed is from about 0:2:1 to about 1:2:0. In some embodiments,compositions comprising mixtures of compounds of Formulas II and III arepreferred, as isolation and purification can be achieved throughprecipitation and recrystallization, and the intermediate compounds ofFormula II can be recovered and recycled. In contrast, compositionscomprising mixtures of compounds of Formulas III and IV requirechromatographic separation to give III along with the undesireddialkylated by-product of Formula IV.

In another embodiment, the desired crude composition, i.e., mixtures ofcompounds of Formula II and compounds of Formula III, wherein R₁ ismethoxy (OCH₃) and R₂ is methyl (CH₃), is obtained through contacting acompound of Formula II with Li₂CO₃ and methyl iodide (CH₃I) in DMF (1.0M) in a molar ratio of about 1:0.6:3 at 45° C. Upon completion, dilutionof the crude composition with a polar, aprotic solvent, such as CH₃CN,wherein the ratio of CH₃CN:DMF is from about 2:1 to about 1:2, followedby an aqueous solution of sodium thiosulfate (Na₂S₂O₃) with a pH fromabout 8 to about 1.0.5, wherein the ratio of 2.5 wt. % aqueousNa₂S₂O₃:DMF is from about 1:2 to about 3:1, affords a precipitate whichis isolable by filtration. In one embodiment, the ratio of CH₃CN:DMF isabout 1:2 and the ratio of 2.5% aqueous Na₂S₂O₃:DMF is about 1:1, andthe resultant solid is further purified by crystallization/precipitationfrom a warmed solution, about 30° C.-40° C., of the solid in a solutionof a polar, aprotic solvent, such as CH₃CN, by the addition of water(H₂O), wherein the ratio of H₂O:CH₃CN is from about 1:2 to about 3:1, togive the purified compound of Formula III, and in another embodiment theratio of H₂O:CH₃CN to affect precipitation of pure III is about 2:1.

In another embodiment, compounds of Formula II may be prepared bycontacting compounds of Formula I (shown below) withbis-N,O-trimethylsilylacetamide (BSA) at an elevated temperature, suchas 70° C., for a period of about 1 hour (h), followed by cooling andcontacting the solution containing the protected pyrimidinol with asubstituted benzene sulfonyl chloride, generalized by R₁-PhSO₂Cl,wherein R₁ is as previously defined, at about 20° C.-25° C. In someembodiments, the molar ratio of the compound of Formula I to BSA and thesulfonyl chloride is about 1:3:1.1, respectively, and in anotherembodiment reducing the molar ratio of the reactants to about 1:1.1:1.1affords improved yields.

The term “alkyl” refers to a branched, unbranched, or saturated cycliccarbon chain, including, but not limited to, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbonchain containing one or more double bonds including, but not limited to,ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “aryl” refers to any aromatic, mono- or bi-cyclic, containingheteroatoms.

The term “heterocycle” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms.

The term “alkoxy” refers to an —OR substituent.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

Throughout the disclosure, references to the compounds of Formulas I,II, III, and IV are read as also including optical isomers and salts.Exemplary salts may include: hydrochloride, hydrobromide, hydroiodide,and the like. Additionally, the compounds of Formulas I, II, III, and IVmay include tautomeric forms.

Certain compounds disclosed in this document can exist as one or moreisomers. It will be appreciated by those skilled in the art that oneisomer may be more active than the others. The structures disclosed inthe present disclosure are drawn in only one geometric form for clarity,but are intended to represent all geometric and tautomeric forms of themolecule.

In one exemplary embodiment, a method of making a compound of FormulaIII is provided. The method includes contacting a compound of Formula IIwith an alkali carbonate and an alkylating agent; and forming a compoundof Formula III,

wherein R₁ is selected from the group consisting of:

andR₂ is selected from the group consisting of:

In a more particular embodiment, the contacting step is carried outbetween 22° C. and 60° C.

In another more particular embodiment of any of the above embodiments,the contacting step further includes a solvent selected from the groupconsisting of DMF, DMSO, DMA, NMP, and CH₃CN.

In another more particular embodiment of any of the above embodiments,the alkali carbonate is selected from the group consisting of Na₂CO₃,K₂CO₃, Cs₂CO₃, and Li₂CO₃.

In another more particular embodiment of any of the above embodiments,the alkylating agent is selected from the group consisting of: alkylhalides and benzyl halides. In an even more particular embodiment, thealkyl halide and benzyl halide are selected from methyl iodide (CH₃I),ethyl iodide (C₂H₅I), and benzyl bromide (BnBr).

In another more particular embodiment of any of the above embodiments,the alkali carbonate base is Cs₂CO₃, and the solvent is DMF.

In another more particular embodiment of any of the above embodiments, amolar ratio of Compound II to alkali carbonate base is from about 3:1 toabout 1:1 and a molar ratio of Compound II to alkylating agent is fromabout 1:1 to about 3:1. In an even more particular embodiment, a molarratio of Compound II to alkali carbonate base is about 2:1 a molar ratioof Compound H alkylating agent is 1:3.

In another more particular embodiment of any of the above embodiments,the method further includes the step of diluting a completed reactionmixture with CH₃CN and 2.5% aqueous Na₂S₂O₃. In an even more particularembodiment, a ratio of DMF to CH₃CN is from about 1:1 to about 3:1 and aratio of DMF to 2.5% aqueous Na₂S₂O₃ is from about 1:2 to about 2:1. Ina still more particular embodiment, a ratio of DMF to CH₃CN is about 2:1and a ratio of DMF to 2.5% aqueous Na₂S₂O₃ is about 1:1.

In another embodiment, a method of preparing a compound of Formula II isprovided. The method includes contacting a compound of Formula I withbis-N,O-trimethylsilylacetamide (BSA):

and forming a compound of Formula II:

wherein a molar ratio of compound I to bis-N,O-trimethylsilylacetamide(BSA) is 1:1.1 and the contacting step is carried out at about 22° C. toabout 70° C.

In a more particular embodiment, the contacting step further includescontacting compound I with CH₃CN.

In another more particular embodiment of any of the above embodiments,the method comprises contacting a BSA treated reaction mixture with anarylsulfonyl chloride.

In another more particular embodiment of any of the above embodiments, amolar ratio of Compound I to arylsulfonyl chloride is from about 1:2 toabout 2:1. In an even more particular embodiment, a molar ratio ofCompound I to arylsulfonyl chloride is 1:1.1.

The embodiments described above are intended merely to be exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the invention and are encompassedby the appended claims.

DETAILED DESCRIPTION

5-Fluoro-4-imino-3-(alkyl/substitutedalkyl)-1-(arylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one as shown inExamples 1-2.

Example 1: Preparation of4-amino-5-fluoro-1-(phenylsulfonyl)pyrimidin-2(1H)-one (1)

To a dry 500 milliliter (mL) round bottom flask equipped with amechanical stirrer, nitrogen inlet, addition funnel, thermometer, andreflux condenser were added 5-fluorocytocine (20.0 grams (g), 155millimole (mmol)) and CH₃CN (100 mL). To the resulting mixture was addedBSA (34.7 g, 170 mmol)) in one portion and the reaction was warmed to70° C. and stirred for 30 minutes (min). The resulting homogeneoussolution was cooled to 5° C. with an ice bath and treated dropwise withbenzenesulfonyl chloride. The reaction was stirred at 0° C.-5° C. for 1h and then overnight at room temperature. The resulting pale yellowsuspension was poured into cold H₂O (1.5 liters (L)) and stirredvigorously for 1 h. The resulting solid was collected by vacuumfiltration, washed with H₂O, and dried under vacuum overnight at 40° C.to give 4-amino-5-fluoro-1-(phenylsulfonyl)pyrimidin-2(1H)-one (29.9 g,72%) as a powdery white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H),8.35-8.26 (m, 2H), 8.07-7.98 (m, 2H), 7.84-7.74 (m, 1H), 7.72-7.61 (m,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −163.46; ESIMS m/z 270 ([M+H]⁺).

The following compounds 1-3 in Table 1a were made in accordance with thereaction depicted in Scheme 1 and the procedures described in Example 1.Characterization data for compounds 1-3 are shown in Table 1b.

TABLE 1a Compound Yield Number R₁ Appearance (%) 1 H Powdery White Solid72 2 CH₃ Powdery White Solid 61 3 OCH₃ Powdery White Solid 57

TABLE 1b ¹³C NMR or Compound Mass ¹⁹F NMR Number Spec. ¹H NMR (δ)^(a)(δ)^(b,c) 1 ESIMS ¹H NMR (DMSO- ¹⁹F NMR m/z 270 d₆) δ 8.56 (s, 1H),(DMSO-d₆) δ −163.46 ([M + H]⁺) 8.35-8.26 (m, 2H), 8.07-7.98 (m, 2H),7.84-7.74 (m, 1H), 7.72-7.61 (m, 2H) 2 ESIMS ¹H NMR (DMSO- ¹⁹F NMR m/z284 d₆) δ 8.54 (s, 1H), (DMSO-d₆) δ −163.62 ([M + H]⁺) 8.40-8.16 (m,2H), 8.05-7.76 (m, 2H), 7.66-7.36 (m, 2H), 2.41 (s, 3H) 3 ESIMS ¹H NMR(CDCl₃) ¹⁹F NMR m/z 300 δ 8.10-7.91 (m, (CDCl₃) δ −158.58 ([M + H]⁺)2H), 7.73 (d, J = 5.4 Hz, 2H), 7.11-6.94 (m, 2H), 3.90 (s, 3H), 3.32 (d,J = 0.6 Hz, 3H) ^(a)All ¹H NMR data measured at 400 MHz unless otherwisenoted. ^(b)All ¹³C NMR data measured at 101 MHz unless otherwise noted.^(c)All ¹⁹F NMR data measured at 376 MHz unless otherwise noted.

Example 2: Preparation of5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one (5)

To a mixture of 4-amino-5-fluoro-1-tosylpyrimidin-2(1H)-one (5.66 g, 20mmol) and Li₂CO₃ (0.880 g, 12.0 mmol) in DMF (20 mL) was added CH₃I(8.52 g, 60.0 mmol), and the resulting mixture was warmed to 40° C. andstirred for 5 h. The reaction mixture was cooled to room temperature,diluted with CH₃CN (10 mL), and treated with 2.5% aqueous Na₂S₂O₃ (20mL). The resulting mixture was stirred at room temperature for 10 minand the solids were collected by filtration. The filter cake was washedwith aqueous CH₃CN (10% CH₃CN in H₂O) and air dried for 2 h. The cakewas dissolved in CH₃CN (15 mL) at 40° C. and the solution was treatedwith H₂O (30 mL). The resulting suspension was cooled to roomtemperature, stirred for 2.5 h, and filtered. The filter cake was againwashed with 10% aqueous CH₃CN and then dried under vacuum at 50° C. togive the title compound (2.70 g, 45%) as a white solid: mp 156-158° C.;³H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=2.3 Hz, 1H), 7.99 (dd, J=6.0, 0.6Hz, 1H), 7.95-7.89 (m, 2H), 7.53-7.45 (m, 2H), 3.12 (d, J=0.7 Hz, 3H),2.42 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) −157.86 (s); ESIMS m/z 298([M+H]⁺).

The following compounds 4-6 in Table 2a were made in accordance with thereaction depicted in Scheme 2 and the procedures described in Example 2.Characterization data for compounds 4-6 are shown in Table 2b.

TABLE 2a Compound Yield Number R₁ R₂ Appearance (%) 4 H CH₃ White Solid64 5 CH₃ CH₃ White Solid 45 6 OCH₃ CH₃ White Solid 62

TABLE 2b ¹³C NMR or Compound Mass ¹⁹F NMR Number Spec. ¹H NMR (δ)^(a)(δ)^(b,c) 4 ESIMS ¹H NMR (CDCl₃) δ ¹⁹F NMR m/z 284 8.14-8.02 (m, 2H),(CDCl₃) δ −158.05 ([M + H]⁺) 7.88-7.67 (m, 3H), 7.67-7.50 (m, 2H), 3.31(d, J = 0.7 Hz, 3H) 5 ESIMS ¹H NMR (DMSO-d₆) ¹⁹F NMR m/z 298 δ 8.54 (d,J = 2.3 Hz, (DMSO-d₆) ([M + H]⁺) 1H), 7.99 (dd, J = 6.0, δ 157.86 (s)0.6 Hz, 1H), 7.95-7.89 (m, 2H), 7.53-7.45 (m, 2H), 3.12 (d, J = 0.7 Hz,3H), 2.42 (s, 3H) 6 ESIMS ¹H NMR (CDCl₃) δ ¹⁹F NMR m/z 314 8.10-7.91 (m,2H), (CDCl₃) δ −158.58 ([M + H]⁺) 7.73 (d, J = 5.4 Hz, 2H), 7.11-6.94(m, 2H), 3.90 (s, 3H), 3.32 (d, J = 0.6 Hz, 3H) ^(a)All ¹H NMR datameasured at 400 MHz unless otherwise noted. ^(b)All ¹³C NMR datameasured at 101 MHz unless otherwise noted. ^(c)All ¹⁹F NMR datameasured at 376 MHz unless otherwise noted.

What is claimed is:
 1. A method of making compounds of Formula III,including the steps of: contacting a compound of Formula II with analkali carbonate and an alkylating agent,

and forming a compound of Formula III:

wherein R₁ is selected from the group consisting of:

and

and R₂ is selected from the group consisting of:

wherein the molar ratio of the compound of Formula II to the alkalicarbonate is from 3:1 to 1:1.
 2. The method of claim 1, wherein a) thecontacting step is carried out between 22° C. and 60° C.; b) thecontacting step further includes a solvent selected from the groupconsisting of: DMF, DMSO, DMA, NMP, and CH₃CN; c) the alkali carbonateis selected from the group consisting of: Na₂CO₃, K₂CO₃, Cs₂CO₃, andLi₂CO₃; d) the alkylating agent is selected from the group consistingof: alkyl halides and benzyl halides; and/or e) the method furtherincludes the step of diluting a completed reaction mixture with CH₃CNand 2.5% aqueous Na₂S₂O₃.
 3. The method of claim 2, wherein the alkylhalides and benzyl halides are selected from the group consisting of:methyl iodide, ethyl iodide, and benzyl bromide.
 4. The method of claim2, wherein the alkali carbonate is Cs₂CO₃, and the solvent is DMF. 5.The method of claim 1, wherein the molar ratio of the compound ofFormula II to the alkylating agent is from 1:1 to 3:1.
 6. The method ofclaim 1, wherein the molar ratio of the compound of Formula II to thealkali carbonate is 2:1 and the molar ratio of the compound of FormulaII to the alkylating agent is 1:3.
 7. The method of claim 3, wherein themethod further includes the step of diluting a completed reactionmixture with CH₃CN and 2.5% aqueous Na₂S₂O₃ and the ratio of DMF toCH₃CN is from 1:1 to 3:1 and the ratio of DMF to 2.5% aqueous Na₂S₂O₃ isfrom 1:2 to 2:1.
 8. A method of preparing a compound of Formula II,including the steps or: contacting a compound of Formula I:

with bis-N,O-trimethylsilylacetamide; and forming a compound of FormulaII:

wherein R₁ is selected from the group consisting of:

and wherein the molar ratio of compound I tobis-N,O-trimethylsilylacetamide is 1:1.1 and the contacting step iscarried out at 22° C. to 70° C.
 9. The method of claim 8, wherein a) thecontacting step further includes contacting compound I with CH₃CN;and/or b) the method further comprises a step of contacting abis-N,O-trimethylsilylacetamide treated reaction mixture with anarylsulfonyl chloride.
 10. The method of claim 9, wherein the molarratio of the compound of Formula I to the arylsulfonyl chloride is from1:2 to 2:1.
 11. The method of claim 2, wherein a) the contacting step iscarried out between 22° C. and 45° C.; b) the solvent selected from thegroup consisting of: DMF, DMA, and NMP; c) the alkali carbonate isLi₂CO₃; and/or d) the alkylating agent is an alkyl halide and the alkylhalide is methyl iodide.
 12. The method of claim 7, wherein the ratio ofDMF to CH₃CN is 2:1 and the ratio of DMF to 2.5% aqueous Na₂S₂O₃ is 1:1.13. The method of claim 10, wherein the molar ratio of the compound ofFormula I to the arylsulfonyl chloride is 1:1.1.